Functional analysis of P-glycoprotein mutants identifies predicted transmembrane domain 11 as a putative drug binding site

Biochemistry ◽  
1993 ◽  
Vol 32 (16) ◽  
pp. 4185-4194 ◽  
Author(s):  
Shama Kajiji ◽  
France Talbot ◽  
Kart Grizzuti ◽  
Valerie Van Dyke-Phillips ◽  
Michael Agresti ◽  
...  
Keyword(s):  
Functional Analysis ◽  
Binding Site ◽  
Transmembrane Domain ◽  
Drug Binding ◽  
Drug Binding Site ◽  
P Glycoprotein

scholarly journals Modulation of drug-stimulated ATPase activity of human MDR1/P-glycoprotein by cholesterol

2006 ◽  
Vol 401 (2) ◽  
pp. 597-605 ◽  
Author(s):  
Yasuhisa Kimura ◽  
Noriyuki Kioka ◽  
Hiroaki Kato ◽  
Michinori Matsuo ◽  
Kazumitsu Ueda
Keyword(s):  
Atpase Activity ◽  
Molecular Mass ◽  
Binding Site ◽  
Drug Binding ◽  
Soluble Form ◽  
Strongly Correlated ◽  
Drug Binding Site ◽  
Hydrophobic Compounds ◽  
P Glycoprotein ◽  
Human Mdr1

MDR1 (multidrug resistance 1)/P-glycoprotein is an ATP-driven transporter which excretes a wide variety of structurally unrelated hydrophobic compounds from cells. It is suggested that drugs bind to MDR1 directly from the lipid bilayer and that cholesterol in the bilayer also interacts with MDR1. However, the effects of cholesterol on drug–MDR1 interactions are still unclear. To examine these effects, human MDR1 was expressed in insect cells and purified. The purified MDR1 protein was reconstituted in proteoliposomes containing various concentrations of cholesterol and enzymatic parameters of drug-stimulated ATPase were compared. Cholesterol directly binds to purified MDR1 in a detergent soluble form and the effects of cholesterol on drug-stimulated ATPase activity differ from one drug to another. The effects of cholesterol on Km values of drug-stimulated ATPase activity were strongly correlated with the molecular mass of that drug. Cholesterol increases the binding affinity of small drugs (molecular mass <500 Da), but does not affect that of drugs with a molecular mass of between 800 and 900 Da, and suppresses that of valinomycin (molecular mass >1000 Da). Vmax values for rhodamine B and paclitaxel are also increased by cholesterol, suggesting that cholesterol affects turnover as well as drug binding. Paclitaxel-stimulated ATPase activity of MDR1 is enhanced in the presence of stigmasterol, sitosterol and campesterol, as well as cholesterol, but not ergosterol. These results suggest that the drug-binding site of MDR1 may best fit drugs with a molecular mass of between 800 and 900 Da, and that cholesterol may support the recognition of smaller drugs by adjusting the drug-binding site and play an important role in the function of MDR1.

scholarly journals Evidence for the Interaction of A3 Adenosine Receptor Agonists at the Drug-Binding Site(s) of Human P-glycoprotein (ABCB1)

2019 ◽  
Vol 96 (2) ◽  
pp. 180-192 ◽  
Author(s):  
Biebele Abel ◽  
Dilip K. Tosh ◽  
Stewart R. Durell ◽  
Megumi Murakami ◽  
Shahrooz Vahedi ◽  
...  
Keyword(s):  
Binding Site ◽  
Adenosine Receptor ◽  
Drug Binding ◽  
Adenosine Receptor Agonists ◽  
Receptor Agonists ◽  
Drug Binding Site ◽  
P Glycoprotein ◽  
A3 Adenosine Receptor
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